Human immunodeficiency
virus (HIV) is not the cause of AIDS because it fails to meet the
postulates of Koch and Henle, as well as six cardinal rules of virology.
1) HIV is in violation of Koch's first postulate
because it is not possible to detect free virus (1, 2), provirus
(3-5), or viral RNA (4, 6, 7) in all cases of AIDS. Indeed, the
Centers for Disease Control (CDC) has established guidelines to
diagnose AIDS when all laboratory evidence for HIV is negative (8).
2) In violation of Koch's second postulate, HIV
cannot be isolated from 20 to 50% of AIDS cases (1, 9-11). Moreover,
"isolation" is very indirect. It depends on activating dormant
provirus in millions of susceptible cells propagated in vitro away
from the suppressive immune system of the host.
3) In violation of Koch's third postulate, pure
HIV does not reproduce AIDS when inoculated into chimpanzees or
accidentally into healthy humans (9, 12, 13).
4) In contrast to all pathogenic viruses that cause
degenerative diseases, HIV is not biochemically active in the disease
syndrome it is named for (14). It actively infects only 1 in 104
to > 105 T cells (4, 6, 7, 15). Under these conditions, HIV cannot
account for the loss of T cells, the hallmark of AIDS, even if all
infected cells died. This is because during the 2 days it takes
HIV to replicate, the body regenerates about 5% of its T cells (16),
more than enough to compensate for losses due to HIV.
5) It is paradoxical that HIV is said to cause AIDS
only after the onset of antiviral immunity, detected by a positive
"AIDS test," because all other viruses are most pathogenic
before immunity. The immunity against HIV is so effective that free
virus is undetectable (see point 1), which is why HIV is so hard
to transmit (9, 12, 13). The virus would be a plausible cause of
AIDS if it were reactivated after an asymptomatic latency, like
herpes viruses. However, HIV remains inactive during AIDS. Thus
the "AIDS test" identifies effective natural vaccination,
the ultimate protection against viral disease.
6) The long and highly variable intervals between
the onset of antiviral immunity and AIDS, averaging 8 years, are
bizarre for a virus that replicates within 1 to 2 days in tissue
culture and induces antiviral immunity within 1 to 2 months after
an acute infection (9, 17). Since all genes of HIV are active during
replication, AIDS should occur early when HIV is active, not later
when it is dormant. Indeed, HIV can cause a mononucleosis-like disease
during the acute infection, perhaps its only pathogenic potential
(9, 17).
7) Retroviruses are typically not cytocidal. On
the contrary, they often promote cell growth. Therefore, they were
long considered the most plausible viral carcinogens (9). Yet HIV,
a retrovirus, is said to behave like a cytocidal virus, causing
degenerative disease killing billions of T cells (15, 18). This
is said even though T cells grown in culture, which produce much
more virus than has ever been observed in AIDS patients, continue
to divide (9, 10, 18).
8) It is paradoxical for a virus to have a country-specific
host range and a risk group-specific pathology. In the United States,
92% of AIDS patients are male (19), but in Africa AIDS is equally
distributed between the sexes, although the virus is thought to
have existed in Africa not much longer than in the United States
(20). In the United States, the virus is said to cause Kaposi's
sarcoma only in homosexuals, mostly Pneumocystis pneumonia in hemophiliacs,
and frequently cytomegalovirus disease in children (21). In Africa
the same virus is thought to cause slim disease, fever, and diarrhea
almost exclusively (22, 23).
9) It is now claimed that at least two viruses,
HIV-1 and HIV-2, are capable of causing AIDS, which allegedly first
appeared on this planet only a few years ago (20). HIV-1 and HIV-2
differ about 60% in their nucleic acid sequences (24). Since viruses
are products of gradual evolution, the proposition that within a
few years two viruses capable of causing AIDS could have evolved
is highly improbable (25).

Biology is an experimental
science, and new biological phenomena are continually being discovered.
For example, recently some RNA molecules were shown to act as enzymes,
ribozymes, even though biochemistry text books state that all enzymes
are proteins. Thus, one cannot conclude that HIV-1 does or does
not cause AIDS from Duesberg's "cardinal rules" of virology.
In fact, the Henle-Koch postulates of 1840 and 1890 were formulated
before the discovery of viruses. They are a useful historical reference
point, but were not regarded as rigid criteria by Koch himself and
should not be so regarded today (1).
Duesberg's description of the properties of viruses
is in error and provides no distinction between knowing the cause
of a disease, that is, its etiology, and understanding the pathogenesis
of this disease. Duesberg is noted for his discoveries about the
viral oncogene src. There is no question that the expression of
this gene in chicken fibroblasts results in sarcomas. However, no
one can yet explain how the expression by the src oncogene of an
altered tyrosine protein kinase results in a cell becoming neoplastic.
Similarly, there are many unanswered questions about the pathogenesis
of AIDS, but they are not relevant to the conclusion that HIV causes
AIDS.
Duesberg presents six (or nine) cardinal rules for
viruses. Most are not relevant to the question of etiology and are
misleading or wrong about viruses in general and HIV in particular.
1-2) It was formerly true that evidence for the
presence of HIV-1 could not be found in all AIDS patients. But the
overwhelming seroepidemiologic evidence pointing toward HIV as the
cause of AIDS spurred research to improve the sensitivity of the
detection methods. Better methods of virus isolation now show that
HIV infection is present in essentially all AIDS patients (2).
The CDC definition of AIDS has been revised several
times as new knowledge has become available and will undoubtedly
be revised again. The 1981 CDC definition of AIDS did not mention
HIV, since no strain of HIV was known until 1983. Many cases of
AIDS are diagnosed on clinical grounds alone because of the lack
of availability or expense of HIV-1 antibody testing or because
HIV testing is discouraged in some communities. Thus, rates of confirmation
of AIDS cases by HIV testing in the United States vary geographically
as reflected in CDC surveillance statistics.
3) It is true that HIV does not cause AIDS in chimpanzees.
Most viruses are species-specific in host range and in capacity
to produce disease. For example, herpes B virus, yellow fever virus,
and dengue virus cause serious diseases in humans, but produce no
disease symptoms during infection in many species of monkeys (3).
Moreover, a virus closely related to HIV, simian immunodeficiency
disease virus or SIV, causes an AIDS-like disease in rhesus macaques,
but seldom, if ever, causes immunodeficiency in African Green monkeys
(4, 5).
HIV-1 does indeed cause AIDS when inoculated into
humans with no underlying medical condition. Accidental needlestick
injuries with HIV-contaminated needles have resulted in HIV seroconversion
and then clinical AIDS (6).
4) It is true that HIV infects only a small fraction
of T cells. However, about 15% of the macrophage and monocyte cells
from AIDS patients are positive for a viral protein, p24 (7), and
the high concentration of this protein in the blood of AIDS patients
indicates virus activity (8). The exact mechanism of CD4 cell depletion
in AIDS patients is not known, but several indirect mechanisms are
known by which HIV can cause CD4 cell depletion in laboratory studies
and could operate in vivo.
5-6) Many viruses are highly pathogenic after evidence
of immunity appears. For example, reactivated herpes zoster virus
causes shingles, and reactivated herpes simplex virus causes local
lesions as well as lethal necrotizing encephalitis; moreover, hepatitis
B virus causes chronic active hepatitis, equine infectious anemia
virus causes anemia, and visna virus causes central nervous system
degeneration after the appearance of specific neutralizing antibodies
(3, 9). (The last two viruses are lentiretroviruses as is HIV.)
These diseases also can have long and variable latent periods.
7) It is true that some retroviruses, in particular,
the highly oncogenic retroviruses of the kind that Duesberg has
worked with, are not cytocidal and promote cell growth. Most retroviruses
have no effect on cell growth (9, 10). However, Rous-associated
virus-2, spleen necrosis virus, visna virus, and HIV kill infected
cells in culture and can establish a chronic stage of infection
in which surviving infected cells continue to divide (11).
8) It was apparently "paradoxical for a virus
to have a country-specific host range and a risk group-specific
pathology." The properties of HIV resolved this paradox because
the distribution of AIDS was found to mirror the distribution of
HIV. The nature of the spread of the virus and the type of the AIDS-related
clinical syndrome depend on social and environmental factors. Sexually
active gay men and parenteral drug abusers were the first conduit
for spread of HIV in the United States, whereas in some developing
countries of Africa, young heterosexually active men and women were
the major focus of spread. It is common for life-style to be a major
determinant for the spread of an infectious agent. For example,
until a vaccine became available, hepatitis B virus was clustered
among the same U.S. populations that are now infected by HIV.
The underlying pathology in AIDS is immune deficiency.
The nature of the opportunistic agents that invade the susceptible
host is a function of which agents are most prominent in a particular
population. For example, in the United States Pneumocystis is most
prominent in affluent gay men, while human mycobacterial infections
and toxoplasmosis are more frequent in socially disadvantaged Caribbean
immigrants. Other agents, such as Cryptococcus, are more prominent
in developing countries.
9) It is true that there are two viruses that cause
human AIDS, HIV-1 and HIV-2. The origin of these HIVs is an interesting
scientific question that is not relevant to whether or not HIV causes
AIDS. Since a primate lentiretrovirus also causes an AIDS-like disease
in rhesus monkeys, just as a cat lentiretrovirus, feline immunodeficiency
virus, causes an AIDS-like disease in cats (12), one can suggest
either that there is strong selection among retroviruses for this
kind of pathology (13) or that the virus ancestor to HIV already
had this property. In favor of the first hypothesis is the existence
of feline, murine, and primate AIDS caused by retroviruses in a
different subfamily from the lentiretroviruses (14).
In summary, although many questions remain about
HIV and AIDS, a huge and continuously growing body of scientific
evidence shows that HIV causes AIDS.

References and Notes:

A.S. Evans, Yale
J. Biol. Med. 49, 175 (1976).

References 1 and
2 from Duesberg report isolation of HIV-1 from 100% of AIDS patients;
I.S.Y. Chen (UCLA) reports isolation of HIV-1 from 100% of AIDS
patients (personal communication); R.C. Gallo, M. Popovic, S.
Z. Salahuddin, S. Gardner, and co-workers now isolate HIV-1 from
more than 90% of AIDS patients. Duesberg's references 5 and
7 do not report on AIDS patients at all.

AIDS Program, Hospital
Infections Branch, CDC, Morbid. Mortal. Weekly Rep. 37, 229 (1988).
This pattern of AIDS development following HIV-1 seroconversion
is the same as that seen for pediatric and adult blood transfusion
cases and mother-to-child transmission, and in a multitude of
prospective studies of gay men, hemophiliacs, and other populations
in developed and developing countries.

AIDS, a new disease, was first recognized in 1981, clustered in
male homosexuals, intravenous drug abusers, and hemophiliacs in
the United States and among sexually active heterosexuals in some
countries of equatorial Africa. Human immunodeficiency virus (HIV)
was first discovered in 1983 and was definitively linked in 1984
to AIDS patients and to groups whose members were at high risk for
developing AIDS. The serological test for antibodies to HIV was
developed at this same time and showed that HIV infection in the
United States was concentrated in those populations at highest risk
for AIDS, namely, male homosexuals, intravenous drug abusers, and
hemophiliacs (1).
The strongest evidence that HIV causes AIDS comes
from prospective epidemiological studies that document the absolute
requirement for HIV infection for the development of AIDS. It has
been shown for every population group studied in the United States
and elsewhere that, in the years following the introduction of HIV
and subsequent seroconversion of members of that population, the
features characteristic of progressive immunodeficiency emerge in
a predictable sequence resulting in clinical AIDS (2-4). Furthermore,
other epidemiological data show that AIDS and HIV infection are
clustered in the same population groups and in specific geographic
locations and in time. Numerous studies have shown that in countries
with no persons with HIV antibodies there is no AIDS and in countries
with many persons with HIV antibodies there is much AIDS (3). Additionally,
the time of occurrence of AIDS in each country is correlated with
the time of introduction of HIV into that country; first HIV is
introduced, then AIDS appears.
It is also noteworthy that HIV infection, and not
infection with any other infectious agent, is linked to blood transfusion-associated
AIDS (5). Similarly, in HIV-infected pregnant women, mother-to-child
perinatal transmission of HIV occurs approximately 50% of the time,
and over 95% of HIV-infected infants develop AIDS by 6 years, while
their uninfected siblings never develop AIDS (3, 6).
Support for the linkage of HIV infection and AIDS
comes as well from the results of public health interventions where
interruption of HIV infection almost completely prevented the further
appearance of AIDS in blood transfusion recipients (4). After the
introduction of the HIV antibody screening test in the United States,
the transmission of HIV in the blood supply in the United States
was reduced from as high as 1 in 1,000 infected units in some high
risk areas to less than an estimated 1 in 40,000 units countrywide
(7). (The recently recognized cases of virus transmission by blood
transfusion are due to donors being missed by current antibody screening
tests during the window of seroconversion. There is a period of
about 4 to 8 weeks in which newly HIV-infected persons are capable
of transmitting HIV, but have not yet developed antibodies.) As
a result of the decrease in blood transfusion-associated transmission
of HIV, the incidence of blood transfusion-associated AIDS among
U.S. newborns showed a decline (4).
Thirteen of the cases of blood transfusion-associated
seroconversion identified since the start of blood bank screening
were recently investigated (7). In one of these cases, the recipient
of one unit of blood was one of a pair of fraternal twins. This
baby seroconverted and developed AIDS without any other risk factor.
Her twin and her mother received no blood products, developed no
HIV antibodies, and remained healthy. The blood donor became HIV
seropositive and developed AIDS.
Scientists conclude that a virus causes a disease
if the virus is consistently associated with the disease and if
disruption of transmission of the virus prevents occurrence of the
disease. HIV can be detected by culture in most AIDS patients and
by culture or polymerase chain reaction in most HIV seropositive
individuals (8, 9). Epidemiological data show that transmission
of HIV results in AIDS and blocking HIV transmission prevents the
occurrence of AIDS. Thus, we conclude that there is overwhelming
evidence that HIV causes AIDS.
Knowledge of the cause of a disease (etiology) is
important for control of that disease and gives a basis for understanding
the pathology of the disease. However, knowing the cause of a disease
does not mean that there is complete understanding of its pathology.
Discovering the pathogenetic mechanisms of HIV in AIDS is a major
focus for research.

References and Notes:

R.C. Gallo and L.
Montagnier, Nature 326, 435 (1987).

J.W. Curran et al.,
Science 239, 610 (1988).

P. Piot et al.,
ibid., p. 573.

J.J. Goedert and
W. Blattner, in AIDS: Etiology, Diagnosis, Treatment, and Prevention,
V.T. DeVita, S. A. Rosenberg, S. Hellman, Eds. (Lippincott, Philadelphia,
1988). This decline in pediatric AIDS became evident before that
in adult AIDS because of the shorter latent period for AIDS in
infants.

Blattner, Gallo, and Temin defend the hypothesis that HIV causes
AIDS only with epidemiology and anecdotal clinical cases in which
AIDS is correlated with antibody to HIV, but not with active virus.
I submit that this is insufficient because such evidence cannot
distinguish between HIV and other causes, unless there is also evidence
for biochemical activity of HIV in AIDS.
1 ) My opponents say that "following introduction
of HIV in a population ... immunodeficiency emerges in a predictable
sequence." Instead, epidemiological surveys show that the annual
incidence of AIDS among persons with antibody to HIV varies from
almost 0 to over 10%, depending on factors defined by lifestyle,
health, gender, and country of residence (see point 8 of my preceding
statement). Among antibody-positive Americans the avenge conversion
rate is 1% [10,000 to 20,000 (1) of 1 to 2 million (2, 3)] but that
of certain hemophiliacs (4) or male homosexuals (5) is 10% or higher.
These discrepancies between the epidemiologies of HIV antibody and
AIDS indicate that neither HIV nor antibody to it is sufficient
to cause AIDS.
2 ) The argument that HIV, "not ... any other
infectious agent," is linked to AIDS in blood transfusion recipients
and in congenitally infected children is presumptuous for several
reasons. Blood transfusion does not distinguish between HIV and
"any other infectious agent" or blood-borne toxin. Further,
it is presumed that the recipient had no risk factors other than
HIV during the average of 8 years between HIV transfusion and AIDS
symptoms. The transfusion evidence would be more convincing if AIDS
appeared soon after a singular transfusion in generally healthy
recipients. Transfusion AIDS cases, however, only occur very late
after infection and mostly in persons with health risks, such as
hemophilia, that are not representative of healthy individuals.
Likewise, it is presumptuous to assume that HIV was the cause of
AIDS in antibody-positive children, of whom 96% had other health
risks, such as mothers who are prostitutes or addicted to intravenously
administered drugs or blood transfusions for the treatment of hemophilia
or other diseases (1, 6). The references to these cases would have
been more convincing if antibody-negative controls had been included,
having none of "the broad range of clinical diseases ... and
the diversity of signs and symptoms of patients infected with HIV"
(6).
3) According to authoritative sources, the primary
defect of AIDS is a T cell deficiency induced by HIV infection (3,
7, 8). Therefore, it comes as a surprise that the primary clinical
symptom of the children with AIDS was a B cell, not a T cell, deficiency
(6). In fact, one of these same sources reports that "to fit
observations from children into definitions for adult patients is
unwise" (3). I wonder whether there is truly any disease that,
in the presence of antibody to HIV, would not be called AIDS.
4) They claim that "interruption of HIV infection
almost completely prevented the further appearance of blood-transfusion-associated
AIDS." However, according to the CDC, transfusion-associated
AIDS cases in adults have doubled to 752 cases and pediatric cases
tripled to 68 in the year ending May 1988 compared to the previous
year (1). This happened 3 years after antibody-positive transfusions
were reduced 40-fold with the AIDS test (9). The steep increase
in transfusion AIDS cases despite the great reduction of HIV-contaminated
transfusions argues directly against HIV as the cause of AIDS.
5) In addition to the correlation that "in countries
with many persons with HIV antibodies there is much AIDS," it
is necessary to demonstrate some HIV-specific biochemical activity
at the onset of AIDS to prove that HIV causes AIDS. All other viruses
and microbes are very active when they cause fatal, degenerative
diseases similar to AIDS. There is also abundant generic evidence
that this activity is necessary for pathogenicity. Antibodies are
evidence for the absence of an active virus, not a prognosis for
future disease or death. Prior claims for etiology without genetic
or molecular evidence for activity proved to be some of the most
spectacular misdiagnoses in virology: (i) Based on epidemiological
evidence, "scientists concluded" that Epstein-Barr virus was
the cause of Burkitt's lymphoma-until the first virus-free lymphomas
were found (10). (ii) On epidemiological grounds, human and bovine
retroviruses were believed to cause leukemia after bizarre latent
periods of up to 40 years in humans (11)-but finding these viruses
in billions of normal cells of millions of asymptomatic carriers
has cast doubt on this view (12). It is scarcely surprising that
these leukemias arose from virus-infected cells. Consistent with
this view, these "viral" leukemias are clonal and not contagious,
behaving like virus-negative leukemias, and the associated "leukemia"
viruses are not biochemically active (12). (iii) "Slow viruses"
were accepted as causes of Alzheimer's, kuru, and Creutzfeldt-Jakob
disease (13) on the basis of the same kind of epidemiology and transmission
evidence used here for HIV-but these viruses have never materialized.
These examples illustrate that correlations without evidence for
biochemical activity are not sufficient to prove "etiology."
6) I fully support the view that "knowledge of
the cause of a disease (etiology) is important for control."
Since the cause of AIDS is debatable, the control of AIDS may not
be achieved by controlling HIV. This is particularly true for the
highly toxic "control" (preventive or therapeutic) of AIDS
with azidothymidine (AZT)-AZT is designed to inhibit viral DNA synthesis
in persons who have antibodies to a virus that is not synthesizing
DNA (14).